Carbocyclic and oxacarbocyclic fumaric acid oligomers

ABSTRACT

The present invention relates to certain carbocyclic and oxacarbocyclic fumaric acid oligomers and the use thereof for preparing a pharmaceutical preparation as well of pharmaceutical preparations containing these compounds.

REFERENCE TO RELATED APPLICATIONS

This application is a 371 continuation of PCT Application PCT/EP03/03498filed Apr. 3, 2003, the text of which is not in English, which PCTApplication claims priority on German Application No. 102 17 314.1,filed Apr. 18, 2002 the text of which is not in English.

The present invention relates to certain carbocyclic and oxacarbocyclicfumaric acid oligomers, to the use thereof for preparing apharmaceutical preparation and to pharmaceutical preparations containingsaid compounds.

For a long time, fumaric acid dialkyl esters as well as fumaric acidmonoalkyl esters and salts thereof have been successfully used fortreating psoriasis. Said use is described in a number of patents, forexample DE-25 30 372, DE 26 21 214 or EP-B-0 312 697.

The use of fumaric acid mono- and diesters is also described for thetreatment of autoimmune diseases such as polyarthritis or multiplesclerosis (cf. DE 197 21 099.6 and DE 198 53 487.6), but also for use intransplantation medicine (cf. DE 198 53 487.6 and DE 198 39 566.3). Theuse of fumaric acid mono- and diesters for the treatment of NF-kappaBmediated diseases and the treatment of mitochondrial diseases is alsoknown from DE 101 01 307.8 and DE 100 00 577.2. However, all the citeddocuments merely describe fumaric acid mono- and diesters, optionally inthe form of certain salts.

Because of their volatility and sublimability, however, theabove-mentioned fumaric acid esters have the disadvantage of beingdifficult to handle when preparing pharmaceutical products, especiallythose in solid form for oral administration. Specifically thepreparation of such products requires protective measures such as theuse of breathing masks, gloves, protective clothing, etc.

In addition, the fumaric acid esters are absorbed in thegastro-intestinal tract after oral administration and taken upunspecifically from the bloodstream by ail body cells. Therefore, it isnecessary to administer high dosages. Such high dosages in turn lead tothe known side effects of a fumaric acid therapy like flush symptoms(reddening) or gastrointestinal irritation (nausea, diarrhea, winds).Even though such side effects may be reduced considerably byadministering the active ingredient in the form of micro-tablets asdescribed in the above-cited prior art, they cannot be avoidedaltogether.

At the same time, the fumaric acid esters are rapidly hydrolysed in theblood and the products of said hydrolysis, alcohol and fumaric acid orfumaric acid monoester, metabolised. In order to maintaintherapeutically effective levels repeated and frequent administration istherefore necessary. Even though a certain adaptation is observedconcerning the side effects, a further reduction of the side effect ratewould be desirable.

In order to avoid these disadvantages fumaric acid mono- and -diamidesare known from non-prepublished DE 101 33 004.9. These amides are formedwith amino acids and preferably with certain peptides. Bonding to apeptide has the objective of specific delivery of the fumaric acidderivative to individual target cells. However, the respective fumaricacid-peptide derivatives have the disadvantage of being expensive toproduce.

Therefore, it is an object of the present invention to provide fumaricacid derivatives, which are more resistant to hydrolysis and easier toproduce and to handle, and to provide the use of such derivatives.

This object is achieved by certain carbocyclic and oxacarbocyclicfumaric acid oligomers, the use thereof for preparing pharmaceuticalpreparations and pharmaceutical preparations containing these oligomers.

More specifically, the present invention, in a first aspect, relates tocarbocyclic and oxacarbocyclic fumaric acid oligomers containing 2 to 10units derived from fumaric acid and/or esters and/or amides as repeatingunits. These carbocyclic and oxacarbocyclic fumaric acid oligomers arepreferably obtained by olefinic polymerization of C—C double bonds orpolarised olefinic polymerisation of the C—C double bonds and carbonyloxygens of the units, respectively. Preferably, these units derived fromfumaric acid are derived from monomers selected from the groupconsisting of fumaric acid, dialkyl fumarates, monoalkyl hydrogenfumarates, fumaric acid monoamides, fumaric acid diamides, monoalkylmonoamido fumarates, and salts and mixtures thereof. More preferably,the oligomer of the invention contains units derived from only one ortwo monomers; most preferably, the oligomer exclusively containsidentical monomer units. Preferably the monomers are not the fumaricacid itself but one of the above-mentioned derivatives, especially themono- or dialkyl fumarates.

The carbocyclic oligomer of the invention is composed or consists of theunits derived from the fumaric acid in such a way that the units arelinked by covalent C—C bonds at the C atoms 2 and 3 of the fumaric acidskeleton so that a carbocyclic oligomer is produced. The C—C bonds maybe generated by olefinic polymerisation of the double bonds. Thecarbocyclic fumaric acid oligomer of the invention preferably does notcontain any olefinic unsaturations in the backbone.

In the carbocyclic oligomers of the invention, the oligomer backbone(the carbocycle) consists of fumaric acid units, i.e. it has a evennumber of C atoms and does not contain any other monomers and/or heteroatoms. At each C atom this backbone is substituted by one of thecarboxylic acid or carboxylic acid amide groups of the fumaric acidmonomer unit(s) of which it is composed. During synthesis, the monomerunits may be present through polymerisation of the derivatives in theform of the esters or amides, but also in the form of salts.

The oxacarbocyclic oligomer of the invention is composed of the fumaricacid-monomers in such a manner that the units are linked by etherbridges at the C atoms 1 and 3. At the same time, the ethylenicunsaturation shifts from the atoms C₂ and C₃ to C₁ and C₂. In the caseof the oxacarbocyclic oligomers of the invention, the ring thereforecontains polyoxypropene units.

The term “oligomer” used herein refers to a number of at least twofumaric acid monomer units. The carbocyclic fumaric acid oligomerusually contains 2 to 10, preferably 2 to 6 and most preferably 2 to 3units derived from fumaric acid. In general, these may polymerise witheach other or be linked for formation of the carbocycle in any stericarrangement. Preferably, all of the carboxylic acid or carboxylic acidamide groups as substituents of the fumaric acid units in the oligomerof the invention are in a trans position to each other, i.e. to each ofthe adjacent carboxylic acid or carboxylic-acid amide groups.

In a preferred embodiment, the invention relates to a carbocyclicfumaric acid oligomer represented by the following formula (I)

wherein the residues R₁ and R₂ are the same or different and areselected from the group consisting of amine-residues (—NR₃R₄), aminoacid residues (—NH—C(COOH)—R₆), peptide residues having 2 to 100 aminoacids, alcohol residues (—OR₅) and a hydroxyl residue,

-   -   n is an integer from 2 to 10 inclusive,    -   the residues R₃ and R₄ are the same or different and are        selected from the group consisting of hydrogen, C₁₋₂₄ alkyl        residues, the phenyl residue and C₆₋₁₀ aralkyl residues,    -   the residue R₅ is selected from the group consisting of        hydrogen, C₁₋₂₄-alkyl residues, the phenyl residue and C₆₋₁₀        aralkyl residues,    -   and the residue R₆ represents a side chain of a natural or        synthetic amino acid.

In a first embodiment, it is preferred that each of the residues R₁ andR₂ independently represent an alcohol or hydroxyl residue. Preferably,R₁ and R₂ are not both hydroxyl. Therefore, the monomer(s) preferablyis/are one or several monoalkyl hydrogen fumarate(s). In anotherembodiment, both residues R₁ and R₂ may represent an alkoxy residue —OR₅which, even more preferably, is identical. In this case, the monomer(s)is/are dialkyl fumarate(s).

Preferably, R₁ and R₂ are independently selected from the groupconsisting of hydroxyl, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,sec-butoxy, tert-butoxy, phenoxy and pentoxy, most preferably methoxyand/or ethoxy. Accordingly, carbocyclic oligomers, derived from dimethylfumarate, diethyl fumarate, methyl ethyl fumarate, methyl hydrogenfumarate and ethyl hydrogen fumarate are especially preferred. Mostpreferred is a carbocyclic fumaric acid oligomer of the formula (I)wherein R₁ and R₂ both identically represent methoxy or ethoxy.

It goes without saying that monomers bearing a carboxy function and thecorresponding polymers of the invention (wherein R₁ and/or R₂═—OH or—O⁻) may be present in the form of their salts. The alkali metal saltssuch as Li, Na, K, the alkaline earth metal salts such as Mg, Ca, andthe salts of physiologically acceptable transition metals, especially Feand Zn, are preferred.

According to a third preferred embodiment, the invention relates to acarbocyclic oligomer, especially of the above formula (I), wherein R₁ isan amine residue —NR₃R₄ or an amino acid-residue —NH—C(COOH)—R₆ boundvia an amide link and R₂ is an amine residue —NR₃R₄, an alcohol residue—OR₅ or —OH.

As defined above, the residue R₆ may be a side chain of any natural orsynthetic amino acid. The amino acid residue may be present in L or Dconfiguration, the L configuration being preferred. Preferably, R₆ isselected from the group consisting of the side chains of Ala, Val, Leu,Ile, Pro, Trp, Phe, Met, Gly, Ser, Tyr, Thr, Cys, Asn, Gln, Asp, Glu,Lys, His, Arg, Orn, Hcy, Hse, Hyp, and Sar.

Preferably, the residues R₃, R₄ and R₅ are the same or different and areselected from the group consisting of hydrogen, methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl,2-hydroxyethyl, 2- or 3-hydroxypropyl, 2,3-dihydroxypropyl,2-methoxyethyl, methoxymethyl and 2- or 3-methoxypropyl.

In an especially preferred embodiment, the invention relates to acarbocyclic fumaric acid oligomer represented by the formula (II)

which may be called r-1,t-2,c-3,t-4-tetrakis(alkoxycarbonyl)cyclobutaneor r-1,t-2,c-3,t-4-cyclobutane tetracarboxylic acid alkyl ester,

-   -   or represented by the formula (III)

which may be calledr-1,t-2,c-3,t-4,c-5,t-6-hexa(alkoxycarbonyl)cyclohexane or r-1,t-2,c-3,t-4,c-5,t-6-cyclohexane hexacarboxylic acid alkyl ester.

Most preferably, the invention relates to a carboxylic fumaric acidoligomer represented by the formula (IIa)

which may be called r-1,t-2,c-3,t-4-tetrakis(methoxycarbonyl)cyclobutaneor r-1,t-2,c-3,t-4-cyclobutane tetracarboxylic acid methyl ester

-   -   or of the formula (IIIa)

which may be calledr-1,t-2,c-3-t-4,c-5,t-6-hexa(methoxycarbonyl)cyclohexane orr-1,t-2,c-3,t-4,c-5,t-6-cyclohexane hexacarboxylic acid methyl ester.

In another preferred embodiment, the invention relates to anoxacarbocyclic fumaric acid oligomer represented by the followingformula (IV)

wherein the residues R₁ and R₂ are the same or different and areselected from the amine residues (—NR₃R₄), amino acid residues(—NH—C(COOH)—R₆), peptide residues having 2 to 100 amino acids, alcoholresidues (—OR₅) and a hydroxyl residue,

-   -   n is an integer from 2 to 10 inclusive,    -   the residues R₃ and R₄ are the same or different and are        selected from the group consisting of hydrogen, C₁₋₂₄ alkyl        residues, the phenyl residue and C₆₋₁₀ aralkyl residues,    -   the residue R₅ is selected from the group consisting of        hydrogen, C₁₋₂₄ alkyl residues, the phenyl residue and C₆₋₁₀        aralkyl residues,    -   and the residue R₆ represents a side chain of a natural or        synthetic amino acid.

Preferably, R₁, R₂, R₃, R₄, R₅, and R₆ are as defined above. Morepreferably, R₁ and R₂ are alkoxy residues —OR₅ or hydroxy, and, mostpreferably, R₁ and R₂ are methoxy or ethoxy (R₁ and R₂ are alkoxy and R₅is methyl or ethyl). The index n preferably is 2 or 3.

According to an especially preferred embodiment, the oxacarbocyclicfumaric acid oligomer is preferably represented by the formula (V)

wherein R₁ and R₂ are defined as above, or the formula (VI)

The compound of the formula (VI) may be calleddimethyl-2,6-dimethoxy-1,5-dioxacyclo-2,6-octadiene-4,8-dicarboxylate ordimethyl-2,6-dimethoxy-1,5-dioxacycloocta-2,6-diene-4,8-dicarboxylate.

The carbocyclic and oxacarbocyclic fumaric acid oligomers of theinvention may be prepared by well known processes for preparing cycliccompounds. For example, they may be prepared with the aid of knowncyclisation agents such as boron compounds, polyphosphoric acids etc.under the usual conditions.

The carbocyclic fumaric acid oligomers of the invention are preferablyprepared by a photopolymerisation process. As is customary in suchprocesses, polymerisation is induced by irradiation of the monomers,usually in the liquid phase and, optionally, in combination with asuitable conventional solvent inert to polymerisation, such as analkane, cycloalkane or aromatic solvent, with light of a wavelength of200 to 700 nm. If desired, conventional polymerisation initiators suchas hydroperoxides, organic peroxides, benzoin methyl ether, benzyl ordiacetyl, etc., and/or sensitisers may be added, for example, in orderto increase the yield of the reaction. Wavelengths in the UV or bluelight range are preferably used for activating the ethylenicunsaturations of the fumaric acid monomer units or other suitablemonomer units.

Another preferred process of preparation is the so-called metathesiswhich, today, is the process practised most frequently for selectivepolymerisations or ring-closure syntheses. The reactions calledmetathesis reactions generally are cyclisations or polymerisationscatalysed by heavy metal. A general overview is given in the article“Die Olefinmetathese—neue Katalysatoren vergröβern dasAnwendungspotential” (Olefin metathesis—new catalysts increase theapplication potential) by M. Schuster and S. Blechert, “Chemie inunserer Zeit”, No. 1, 2001.

Metathesis reactions for preparing the fumaric acid oligomers of theinvention may be carried out as homogenous or heterogeneous reactionsunder the usual conditions and using conventional catalysts. Exemplarycatalysts that may be mentioned are those on the basis of Pd, Mo and Ru,especially Grubb's catalyst and Schrock's catalyst. The metatheses maybe carried out in conventional solvents such as hydrocarbons (optionallyhalogenated), especially alkanes, cycloalkanes, aromatic solvents, butalso ethers, esters, DMSO, etc. In general, reaction temperatures arebelow room temperature, for example between −20 and 10° C.

The carbocyclic fumaric acid oligomers of the invention may also beprepared by combining the above-mentioned processes, for examplestarting with photopolymerisation in order to obtain cyclic and/orlinear polymers, followed by ring-closure metathesis, possibly in theform of cleaving the cyclisised molecule (cf. J. Pernerstorfer, M.Schuster and S. Blechert in “Cyclisation/cleavage of macrocycles by ringclosing metathesis on solid support-confirmational studies”, Chem.Commun. 1997, 1949).

In a second aspect, the invention relates to the use of a carbocyclicfumaric acid oligomer as defined above for preparing a pharmaceuticalpreparation. In a third aspect, the present invention also relates to apharmaceutical preparation containing a fumaric acid oligomer as definedabove.

The pharmaceutical preparation is preferably intended for treating anautoimmune disease, for use in transplantation medicine and for treatingmitochondrial diseases and diseases which may be influenced by NFkappaB.In particular, the pharmaceutical preparation is suitable and destinedfor

-   -   (1) for the therapy of an autoimmune disease selected from the        group consisting of polyarthritis, multiple sclerosis,        graft-versus-host reactions, juvenile-onset diabetes,        Hashimoto's thyroiditis, Grave's disease (Basedow disease),        systemic Lupus erythematodes (SLE), Sjogren's syndrome,        pernicious anaemia and chronic active (=lupoid) hepatitis;    -   (2) for use in transplantation medicine (host-versus-graft        reactions);    -   (3) for the therapy of mitochondrial diseases selected from the        group consisting of Parkinson syndrome, Alzheimer's disease,        Chorea Huntington disease, retinopathia pigmentosa or forms of        mitochondrial encephalomyopathy; as well as    -   (4) for the therapy of NF-kappaB mediated diseases selected from        the group consisting of progressive systemic sclerodermia,        osteochondritis syphilitica (Wegener's disease), cutis marmorata        (livedo reticularis), Behcet disease, panarteriitis, colitis        ulcerosa, vasculitis, osteoarthritis, gout, arteriosclerosis,        Reiter's disease, pulmonary granulomatosis, types of        encephalitis, endotoxic shock (septic-toxic shock), sepsis,        pneumonia, encephalomyelitis, anorexia nervosa, hepatitis (acute        hepatitis, chronic hepatitis, toxic hepatitis, alcohol-induced        hepatitis, viral hepatitis, jaundice, liver insufficiency and        cytomegaloviral hepatitis), Rennert T-lymphomatosis, mesangial        nephritis, post-angioplastic restenosis, reperfusion syndrome,        cytomegaloviral retinopathy, adenoviral diseases such as        adenoviral colds, adenoviral pharyngoconjunctival fever and        adenoviral ophthalmia, AIDS, Guillain-Barré syndrome,        post-herpetic or post-zoster neuralgia, inflammatory        demyelinising polyneuropathy, mononeuropathia multiplex,        mucoviscidosis, Bechterew's disease, Barett oesophagus, EBV        (Epstein-Barr virus) infection, cardiac remodeling, interstitial        cystitis, diabetes mellitus type II, radiosensitisation of        malignant tumours, multi-resistance of malignant cells to        chemotherapeutic agents (multipharmaceutical preparation        resistance in chemotherapy), granuloma annulare and cancers such        as mamma carcinoma, colon carcinoma, melanoma, primary liver        cell carcinoma, adenocarcinoma, kaposi's sarcoma, prostate        carcinoma, leukaemia such as acute myeloid leukaemia, multiple        myeloma (plasmocytoma), Burkitt lymphoma and Castleman tumour.

The pharmaceutical preparation may be present in a form suitable fororal, rectal, transdermal, ophthalmological, nasal, pulmonary orparenteral application. Preferably, the pharmaceutical preparation issuitable for oral administration; in that case it may be present in theform of tablets, coated tablets, capsules, granulate, solutions fordrinking, liposomes, nano-particles, nano-capsules, micro-capsules,micro-tablets, pellets or powders as well as granulate filled incapsules, micro-tablets filled in capsules, pellets filled in capsules,nano-particles filled in capsules or powder filled in capsules.Preferably, the pharmaceutical preparation is present in the form ofnano-particles, micro-pellets or micro-tablets which, optionally, may befilled in sachets or capsules. As a rule, these micro-pellets ormicro-tablets have a diameter (without coating) of ≦5000 μm, preferably300 to 2000 μm.

Preferably, all solid oral dosage forms may be provided with an entericcoating. For example, this may be applied to the tablets, micro-tablets,micro-pellets etc., or coated onto the capsules containing them.

The forms of the pharmaceutical preparations of the invention maygenerally be prepared by the classic tabletting method, but also bydirect compression, by the melt method in case of solid dispersions andby the spray drying method. If desired, an enteric coating may beapplied in a conventional coating pan, sprayed on or applied in afluid-bed apparatus. After drying is completed, a film coat may beapplied in the same apparatus. If a mixture of active ingredients isused, it is possible to prepare pellets with the individual activeingredients and mixing them in the desired ratio, optionally afterapplying a film coat.

In case of parenteral application, the pharmaceutical preparation ispresent in a suitable form, for example as a sterile solution oremulsion. The correct formulations and suitable excipients are known tothe skilled practitioner.

The pharmaceutical preparation of the invention contains an amount ofoligomer suitable for the therapeutic purpose. This amount may bedetermined by the skilled practitioner by routine experimentation. As arule, the pharmaceutical preparation will contain an amount of fumaricacid oligomer corresponding to 10 to 500 mg of fumaric acid, preferably30 to 200 mg of fumaric acid, most preferably 100 mg of fumaric acid.

When compared with the known use of the monomers as activepharmaceutical preparation ingredients, the use of the oligomers of theinvention has the advantage that, owing to their higher molecularweight, they are less volatile and therefore easier to handle duringproduction and processing. The have the added benefit that, beingsynthetic substances, they have to be converted to endogenous substancesin the body first, which increases their residence time in the organism.This conversion probably takes place by cleaving the substance intomonomers. Owing to the oligomerisation, they also have the advantage ofbeing less irritating on the mucous membrane and therefore have fewerside effects.

The invention will now be illustrated by the following examples whichshould not be construed as limiting.

EXAMPLES Example 1 Preparation of Enteric-Coated Micro-Tablets inCapsules, Containing 60.0 mg ofr-1,t-2,c-3,t-4-tetrakis(methoxycarbonyl)cyclobutane and 30.0 mg ofr-1,t-2,c-3, t-4,c-5,t-6-hexa(methoxycarbonyl)cyclohexane

6.0 kg of r-1,t-2,c-3,t-4-tetrakis(methoxycarbonyl)cyclobutane and 3.0kg of r-1,t-2, c-3,t-4,c-5,t-6-hexa(methoxycarbonyl)cyclohexane arecrushed, mixed thoroughly and homogenised by means of a sieve 800. Thenan excipient mixture with the following composition is prepared: 18.00kg of starch derivative (STA-RX® 1500), 0.30 kg of micro-crystallinecellulose (Avicel PH 101), 0.75 kg of PVP (Kollidon 120), 4.00 kg ofPrimogel, 0.25 kg of colloidal silicic acid (Aerosil). The activeingredient is added to the entire powder mixture, mixed, homogenised bymeans of a sieve 200, processed in the usual manner with a 2% aqueoussolution of polyvinyl pyrrolidone (Kollidon K25) to obtain a bindergranulate and then mixed in the dry state with the outer phase. Saidouter phase consists of 0.50 kg of Mg stearate and 1.50 kg of talcum.Then the powder mixture is compressed in the usual manner to obtainconvex tablets having a gross weight of 10.0 mg and a diameter of 2.0mm.

In order to achieve resistance to gastric acid a solution of 2.250 kg ofhydroxy propyl methyl cellulose phthalate (HPMCCP, Pharmacoat® HP 50) isdissolved in portions in a mixture of the following solvents: 13.00 l ofacetone, 13.50 l of dissolved ethanol (94 wt.-%, denatured with 2% ofketone) and 2.50 l of demineralised water. As a plasticiser, castor oil(0.240 kg) is added to the finished solution and applied in portionsonto the tablet cores in the customary manner.

After drying is completed, a suspension of the following composition isapplied as a film coat in the same apparatus: 0.340 kg of talcum, 0.400kg of titanium(VI) oxide Cronus RN 56, 0.324 kg of coloured lacquerL-Rotlack 86837, 4.800 kg of Eudragit E 12.5% and 0.120 kg ofpolyethylene glycol 6000, pH 11 XI in a solvent mixture of the followingcomposition: 8.170 kg of 2-propanol, 0.200 kg of demineralised water and0.600 kg of glycerine triacetate (Triacetin).

After being analysed for their content of the active ingredient, theenteric-coated micro-tablets are filled into hard gelatine capsules atthe appropriate net weight and sealed.

Example 2 Preparation of Enteric-Coated Micro-Tablets in Capsules,Containing 60.0 mg of r-1,t-2,c-3t-4-tetrakis(methoxycarbonyl)cyclobutane and 30.0 mg ofr-1,t-2,c-3,t-4,c-5 t-6-hexa(methoxycarbonyl)cyclohexane

6.0 kg of r-1,t-2,c-3,t-4-tetrakis(methoxycarbonyl)cyclobutane and 3.0kg of r-1,t-2,c-3,t-4,c-5,t-6-hexa(methoxycarbonyl)cyclohexane arecrushed, mixed thoroughly and homogenised by means of a sieve 800. Thenan excipient mixture with the following composition is prepared: 24.70kg of micro-crystalline cellulose (Avicel PH 200), 3.00 kg ofcroscarmellose sodium (AC-Di-SOL-SD-711), 2.50 kg of talcum, 0.10 kg ofanhydrous silica (Aerosil 200) and 1.00 kg of magnesium stearate. Theactive ingredient is added to the entire powder mixture, mixed andhomogenised. Then the powder mixture is compressed by the directtabletting method to obtain convex micro-tablets having a gross weightof 10.0 mg and a diameter of 2.0 mm.

As an enteric coating, a solution of 0.94 kg of Eudragit L inisopropanol is prepared which also contains 0.07 kg of dibutylphthalate. This solution is sprayed onto the tablet cores. After that, adispersion of 17.32 kg of Eudragit L D-55 and a mixture of 2.80 kg ofmicro-talcum, 2.00 kg of Macrogol 6000 and 0.07 kg of dimeticon in wateris prepared and sprayed onto the cores.

After being analysed for their content of the active ingredient, theenteric-coated micro-tablets are filled into hard gelatine capsules orsachets at the appropriate net weight and sealed.

Example 3 Preparation of Enteric-Coated Pellets in Capsules, Containing60.0 mg of r-1,t-2,c-3,t-4-tetrakis(methoxycarbonyl)cyclobutane and 30.0mg of r-1,t-2,c-3,t-4,c-5, t-6-hexa(methoxycarbonyl)cyclohexane

6.0 kg of r-1,t-2,c-3,t-4-tetrakis(methoxycarbonyl)cyclobutane and 3.0kg of r-1,t-2,c-3,t-4,c-5,t-6-hexa(methoxycarbonyl)cyclohexane arecrushed, mixed thoroughly and homogenised by means of a sieve 800. Atthe same tire, 2 l of a 20% (m/v) polyvinylpyrrolidone solution(Kollidon K30) in ethanol is prepared. 7.250 kg of nonpareilles pelletsare coated in a coating pan and sprayed with one part of the KollidonK-30 solution until slightly humid. After that, portions of the activeingredient mixture are added until the pellets are dry. This process ofhumidification/drying is continued until all of the active ingredientmixture has been added. The remainder of the PVP solution is mixed with0.720 kg of Eudragit E 12.5% solution and all of it sprayed onto thepellets. The pellets are moved around until fully dry.

The pellets are sprayed with Eudragit S 12.5% solution and dried withtalcum. After each spraying/drying cycle, the release of the activeingredients is measured and additional Eudragit S 12.5% solution/talcumadded until a release meeting the specification is obtained.

After being analysed for their content of the active ingredient, theenteric-coated pellets are filled into capsules at the appropriate netweight.

Example 4 Preparation of Enteric-Coated Tablets Containing 120.0 mg ofr-1,t-2,c-3,t-4-tetrakis(methoxycarbonyl)cyclobutane

12.0 kg of r-1,t-2,c-3,t-4-tetrakis(methoxycarbonyl)cyclobutane arecrushed, mixed thoroughly and homogenised by means of a sieve 800. Thenan excipient mixture with the following composition is prepared: 19.00kg of starch derivative (STA-RX 1500®), 2.000 kg of micro-crystallinecellulose (Avicel PH 101®), 0.600 kg of polyvinyl pyrrolidone (PVP,Kollidon® 25), 4.000 kg of Primogel®, 0.300 kg of colloidal silicic acid(Aerosil®). The active ingredient is added to the entire powder mixture,mixed, homogenised by means of a sieve 200, and processed in the usualmanner with a 2% aqueous solution of polyvidon pyrrolidone (PVP,Kollidon® 25) to obtain a binder granulate and then mixed in the drystate with the outer phase. Said outer phase consists of 2.000 kg of aso-called FST complex containing 80% of talcum, 10% of silicic acid and10% Mg stearate. Then the powder mixture is compressed in the usualmanner to obtain convex tablets having a gross weight of 400 mg and adiameter of 11.5 mm.

A solution of 2.250 kg of hydroxy propyl methyl cellulose phthalate(HPMCP, Pharmacoat HP® 50) is dissolved in a mixture of the followingsolvents: 2.50 l of demineralised water, 13.00 l of acetone Ph.Helv.VIIand 13.00 l of ethanol, 94 wt.-% and 0.240 kg of castor oil (Ph.Eur.II)are added to the solution. In a coating pan, the solution is coated ontoor sprayed on the tablet cores in the traditional manner.

After drying is completed, a film coat is applied which is composed of asolution of 4.800 kg of Eudragit E® 12.5%, 0.340 kg of talcum Ph.Eur.II, 0.520 kg of titanium(VI) oxide Cronus RN 56®, 0.210 kg of colouredlacquer ZLT-2 blue (Siegle), and 0.120 kg of polyethylene glycol 6000,Ph.Helv. VII in a solvent mixture of the following composition: 8.200 kgof 2-propanol Ph. Helv. VII, 0.060 kg of glycerine triacetate(Triacefin®) and 0.200 kg of demineralised water. After homogenousdistribution in a fluidised bed, drying and polishing occurs as usual.

Example 5 Preparation of a Suspension for Parenteral Application,Containing 60.0 mg ofr-1,t-2,c-3,t-4-tetrakis(methoxycarbonyl)cyclobutane and 30.0 mg ofr-1,t-2, c-3,t-4,c-5,t-6-hexa(methoxycarbonyl)cyclohexane

Ingredients mg/ml r-1, t-2, c-3,t-4-tetrakis(methoxycarbonyl)cyclobutane 60.00 r-1, t-2, c-3, t-4, c-5,t-6-hexa(methoxycarbonyl)cyclohexane 30.00 Methyl cellulose 0.25 Sodiumcitrate, dihydrate 30.00 Benzyl alcohol 9.00 Methylparaben 1.80Propylparaben 1.20 Water for injection purposes q.s.a.d. 1.00Using standard techniques, the above-mentioned ingredients are processedinto a parenteral suspension.

Example 6 Preparation of a Solution for Parenteral Application,Containing 30.0 mg ofr-1,t-2,c-3,t-4-tetrakis(methoxycarbonyl)cyclobutane

Ingredients mg/ml r-1, t-2, c-3,t-4-tetrakis(methoxycarbonyl)cyclobutane 30.00 Hydroxypropylβ-cyclodextrine 300.00 Sodium dihydrogen phosphate 10.00 Methylparaben0.75 Monothioglycerol 2.00 Water for injection purposes q.s.a.d. 1.00Using standard techniques, the above-mentioned ingredients are processedinto a parenteral solution.

1. A pharmaceutical preparation comprising an oligomer of formula (I)

wherein n is 2 or 3, R₁ is hydroxyl, R₂ is an alcohol radical (—OR₅),and R₅ is a C₁₋₂₄ alkyl radical, with the proviso that when n is 2, R₅is not methyl; or n is 3, R₁ is hydroxyl, R₂ is an amine radical(—NR₃R₄) wherein R₃ and R₄ are the same or different and areindependently chosen from hydrogen, C₁₋₂₄ alkyl radicals, a phenylradical and C₆₋₁₀ aralkyl radicals; or n is 2 or 3, R₁ is an alcoholradical (—OR₅), R₅ is a C₁₋₂₄ alkyl radical, and R₂ is an amine radical(—NR₃R₄) wherein R₃ and R₄ are the same or different and areindependently chosen from hydrogen, C₁₋₂₄ alkyl radicals, a phenylradical and C₆₋₁₀ aralkyl radicals, or n is 2 or 3, R₁ and R₂ areindependently chosen from alcohol radicals (—OR₅), wherein R₅ is a C₁₋₂₄alkyl radical and wherein R₁ and R₂ are different and at least oneexcipient.
 2. A pharmaceutical preparation according to claim 1 whereinthe carbonyl groups carrying the radicals R₁ and R₂ are arranged assubstituents in the trans position to each adjacent substituent.
 3. Apharmaceutical preparation according to claim 1 wherein the oligomer offormula (I) is represented by formula (II)


4. A pharmaceutical preparation according to claim 1 wherein theoligomer of formula (I) is represented by formula (III)


5. A pharmaceutical preparation according to claim 1, saidpharmaceutical preparation being available in a form suitable for oral,rectal, transdermal, dermal, opthalmological, nasal, pulmonary orparenteral application.
 6. A pharmaceutical preparation according toclaim 1, said pharmaceutical preparation being present in the form oftablets, coated tablets, capsules, granulate, solutions for drinking,liposomes, nano-particles, nano-capsules, micro-capsules, micro-tablets,pellets, powders, granulate filled in capsules, micro-tablets filled incapsules, pellets filled in capsules, nano-particles filled in capsulesor powder filled in capsules.
 7. A pharmaceutical preparation accordingto claim 6, said pharmaceutical preparation being present in the form ofnano-particles, micro-pellets or micro-tablets.
 8. A pharmaceuticalpreparation according to claim 6 wherein the solid oral dosage formsfurther comprise an enteric coating.
 9. A pharmaceutical preparationaccording to any of the claims 1 to 8 which contains an amount of anoligomer corresponding to 10 to 500 mg of fumaric acid.
 10. A method forpreparing a pharmaceutical preparation comprising admixing an oligomerof formula (I)

wherein n is 2 or 3, R₁ is hydroxyl, R₂ is an alcohol radical (—OR₅),and R₅ is a C₁₋₂₄ alkyl radical, with the proviso that when n is 2, R₅is not methyl; or n is 3, R₁ is hydroxyl, R₂ is an amine radical(—NR₃R₄) wherein R₃ and R₄ are the same or different and areindependently chosen from hydrogen, C₁₋₂₄ alkyl radicals, a phenylradical and C₆₋₁₀ aralkyl radicals; or n is 2 or 3, R₁ is an alcoholradical (—OR₅), R₅ is a C₁₋₂₄ alkyl radical, and R₂ is an amine radical(—NR₃R₄) wherein R₃ and R₄ are the same or different and areindependently chosen from hydrogen, C₁₋₂₄ alkyl radicals, a phenylradical and C₆₋₁₀ aralkyl radicals, or n is 2 or 3, R₁ and R₂ areindependently chosen from alcohol radicals (—OR₅), wherein R₅ is a C₁₋₂₄alkyl radical and wherein R₁ and R₂ are different with at least oneexcipient.
 11. A pharmaceutical preparation according to claim 7,wherein said nano-particles, micro-pellets or micro-tablets are filledin sachets or capsules.
 12. A method for preparing a pharmaceuticalpreparation according to claim 10 further comprising subjecting theadmixture to tabletting, direct compression, melt methods, or spraydrying to form tablets, granulates, nano-particles, nano-capsules,micro-capsules, micro-tablets, pellets, or powders.
 13. A method forpreparing a pharmaceutical preparation according to claim 12, whereinsaid tablets, granulates, nano-particles, nano-capsules, micro-capsules,micro-tablets, pellets, or powders are enterically coated.
 14. A methodfor preparing a pharmaceutical preparation according to claim 12,wherein said nano-particles, nano-capsules, micro-capsules,micro-tablets, pellets, or powders are put into capsules.
 15. Apharmaceutical preparation comprising an oligomer of formula (I)

wherein n is 2 or 3, R₁ is hydroxyl, R₂ is an alcohol radical (—OR₅),and R₅ is a C₁₋₂₄ alkyl radical, with the proviso that when n is 2, R₅is not methyl and at least one excipient.
 16. A pharmaceuticalpreparation comprising an oligomer of formula (I)

wherein n is 3, R₁ is hydroxyl, R₂ is an amine radical (—NR₃R₄), and R₃and R₄ are the same or different and are independently chosen fromhydrogen, C₁₋₂₄ alkyl radicals, a phenyl radical and C₆₋₁₀ aralkylradicals, and at least one excipient.
 17. A pharmaceutical preparationcomprising an oligomer of formula (I)

wherein n is 2 or 3, R₁ is an alcohol radical (—OR₅), R₅ is a C₁₋₂₄alkyl radical, and R₂ is an amine radical (—NR₃R₄), wherein R₃ and R₄are the same or different and are independently chosen from hydrogen,C₁₋₂₄ alkyl radicals, a phenyl radical and C₆₋₁₀ aralkyl radicals, andat least one excipient.